scholarly journals The Poxvirus Protein A52R Targets Toll-like Receptor Signaling Complexes to Suppress Host Defense

2003 ◽  
Vol 197 (3) ◽  
pp. 343-351 ◽  
Author(s):  
Mary T. Harte ◽  
Ismar R. Haga ◽  
Geraldine Maloney ◽  
Pearl Gray ◽  
Patrick C. Reading ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Interleukin 1 ◽  
Tumor Necrosis Factor Receptor ◽  
Nuclear Factor Κb ◽  
Innate Immune ◽  
Altered Gene Expression ◽  
Altered Gene ◽  
Molecular Patterns ◽  
Transcription Factor Nuclear Factor ◽  
Necrosis Factor

Toll-like receptors (TLRs) are crucial in the innate immune response to pathogens, in that they recognize and respond to pathogen associated molecular patterns, which leads to activation of intracellular signaling pathways and altered gene expression. Vaccinia virus (VV), the poxvirus used to vaccinate against smallpox, encodes proteins that antagonize important components of host antiviral defense. Here we show that the VV protein A52R blocks the activation of the transcription factor nuclear factor κB (NF-κB) by multiple TLRs, including TLR3, a recently identified receptor for viral RNA. A52R associates with both interleukin 1 receptor–associated kinase 2 (IRAK2) and tumor necrosis factor receptor–associated factor 6 (TRAF6), two key proteins important in TLR signal transduction. Further, A52R could disrupt signaling complexes containing these proteins. A virus deletion mutant lacking the A52R gene was attenuated compared with wild-type and revertant controls in a murine intranasal model of infection. This study reveals a novel mechanism used by VV to suppress the host immunity. We demonstrate viral disabling of TLRs, providing further evidence for an important role for this family of receptors in the antiviral response.

Bacterial lipopolysaccharide directly induces angiogenesis through TRAF6-mediated activation of NF-κB and c-Jun N-terminal kinase

Blood ◽  
2003 ◽  
Vol 102 (5) ◽  
pp. 1740-1742 ◽  
Author(s):  
Ingrid Pollet ◽  
Christy J. Opina ◽  
Carla Zimmerman ◽  
Kevin G. Leong ◽  
Fred Wong ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Tumor Necrosis Factor Receptor ◽  
Nuclear Factor Κb ◽  
Dominant Negative ◽  
Bacterial Lipopolysaccharide ◽  
Intracellular Signaling Pathway ◽  
Necrosis Factor

AbstractThe intracellular pathways by which inflammatory mediators transmit their angiogenic signals is not well studied. The effects of a potent inflammatory mediator, bacterial lipopolysaccharide (LPS), are transmitted through Toll-like receptors (TLRs). A major, although not exclusive, LPS/TLR intracellular signaling pathway is routed through TNF (tumor necrosis factor) receptor associated factor 6 (TRAF6). In this report we demonstrate that LPS directly stimulates endothelial sprouting in vitro. By blocking TRAF6 activity using retroviral expression of a dominant-negative TRAF6 in endothelial cells, we show that TRAF6 is absolutely required for the LPS-initiated angiogenic response in vitro and in vivo. Inhibition of either c-Jun N-terminal kinase (JNK) activity or nuclear factor κB (NF-κB) activity, downstream of TRAF6, is sufficient to inhibit LPS-induced endothelial sprouting. In contrast, only inhibition of NF-κB, but not JNK, activity blocks basic fibroblast growth factor (bFGF)–induced angiogenesis. Our findings thus demonstrate a direct endothelial-stimulatory role of LPS in initiating angiogenesis through activation of TRAF6-dependent signaling pathways.

scholarly journals The Human Toll Signaling Pathway: Divergence of Nuclear Factor κB and JNK/SAPK Activation Upstream of Tumor Necrosis Factor Receptor–associated Factor 6 (TRAF6)

1998 ◽  
Vol 187 (12) ◽  
pp. 2097-2101 ◽  
Author(s):  
Marta Muzio ◽  
Gioacchino Natoli ◽  
Simona Saccani ◽  
Massimo Levrero ◽  
Alberto Mantovani
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Interleukin 1 ◽  
Tumor Necrosis Factor Receptor ◽  
Nuclear Factor Κb ◽  
Dominant Negative ◽  
Nuclear Factor ◽  
Kinase C ◽  
Toll Signaling ◽  
Necrosis Factor

The human homologue of Drosophila Toll (hToll) is a recently cloned receptor of the interleukin 1 receptor (IL-1R) superfamily, and has been implicated in the activation of adaptive immunity. Signaling by hToll is shown to occur through sequential recruitment of the adapter molecule MyD88 and the IL-1R–associated kinase. Tumor necrosis factor receptor–activated factor 6 (TRAF6) and the nuclear factor κB (NF-κB)–inducing kinase (NIK) are both involved in subsequent steps of NF-κB activation. Conversely, a dominant negative version of TRAF6 failed to block hToll-induced activation of stress-activated protein kinase/c-Jun NH2-terminal kinases, thus suggesting an early divergence of the two pathways.

scholarly journals Geranylgeraniol Suppresses the Expression of IRAK1 and TRAF6 to Inhibit NFκB Activation in Lipopolysaccharide-Induced Inflammatory Responses in Human Macrophage-Like Cells

2019 ◽  
Vol 20 (9) ◽  
pp. 2320 ◽  
Author(s):  
Puspo E. Giriwono ◽  
Hitoshi Shirakawa ◽  
Yusuke Ohsaki ◽  
Shoko Sato ◽  
Yukihide Aoyama ◽  
...  
Keyword(s):  
Immune Responses ◽  
Nuclear Factor Kappa B ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Tumor Necrosis Factor Receptor ◽  
Innate Immune ◽  
Human Macrophage ◽  
Signaling Proteins ◽  
Innate Immune Responses ◽  
Necrosis Factor

Geranylgeraniol (GGOH), a natural isoprenoid found in plants, has anti-inflammatory effects via inhibiting the activation of nuclear factor-kappa B (NFκB). However, its detailed mechanism has not yet been elucidated. Recent studies have revealed that isoprenoids can modulate signaling molecules in innate immune responses. We found that GGOH decreased the expression of lipopolysaccharide (LPS)-induced inflammatory genes in human macrophage-like THP-1 cells. Furthermore, we observed that the suppression of NFκB signaling proteins, in particular interleukin-1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6), occurred in GGOH-treated cells prior to LPS stimulation, suggesting an immunomodulatory effect. These results indicate that GGOH may modulate and help prevent excessive NFκB activation that can lead to numerous diseases.

scholarly journals The immunological significance of tumor necrosis factor receptor-associated factors (TRAFs)

2021 ◽  
Author(s):  
Takanori So
Keyword(s):  
Tumor Necrosis Factor ◽  
Intracellular Signaling ◽  
Tumor Necrosis ◽  
Interleukin 1 ◽  
Tumor Necrosis Factor Receptor ◽  
The Body ◽  
Cellular Expression ◽  
Functional Aspects ◽  
Tnfr Superfamily ◽  
Necrosis Factor

Abstract The tumor necrosis factor receptor (TNFR)-associated factor (TRAF) family of molecules are intracellular signaling adaptors and control diverse signaling pathways mediated not only by the TNFR superfamily and the Toll-like receptor/interleukin-1 receptor superfamily but also by unconventional cytokine receptors such as IL-6 and IL-17 receptors. There are seven family members, TRAF1 to TRAF7, in mammals. Exaggerated immune responses induced through TRAF signaling downstream of these receptors often lead to inflammatory and autoimmune diseases including rheumatoid arthritis, inflammatory bowel disease, psoriasis and autoinflammatory syndromes, and thus those signals are major targets for therapeutic intervention. For this reason, it has been very important to understand signaling mechanisms regulated by TRAFs that greatly impact on life/death decisions and the activation, differentiation and survival of cells of the innate and adaptive immune systems. Accumulating evidence suggests that dysregulated cellular expression and/or signaling of TRAFs causes overproduction of proinflammatory cytokines, which facilitates aberrant activation of immune cells. In this review, I will explain the structural and functional aspects that are responsible for the cellular activity and disease outcomes of TRAFs, and summarize the findings of recent studies on TRAFs in terms of how individual TRAF family molecules regulates biological and disease processes in the body in both positive and negative ways. This review also discusses how TRAF mutations contribute to human disease.

scholarly journals Anti-Amnesic Effect of Walnut via the Regulation of BBB Function and Neuro-Inflammation in Aβ1-42-Induced Mice

Antioxidants ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 976
Author(s):  
Jong Min Kim ◽  
Uk Lee ◽  
Jin Yong Kang ◽  
Seon Kyeong Park ◽  
Eun Jin Shin ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Protective Effect ◽  
Tumor Necrosis ◽  
Juglans Regia ◽  
Interleukin 1 ◽  
Tumor Necrosis Factor Receptor ◽  
Heme Oxygenase 1 ◽  
Necrosis Factor Alpha ◽  
Amnesic Effect ◽  
Necrosis Factor

This study was conducted to assess the protective effect of walnut (Juglans regia L.) extract on amyloid beta (Aβ)1-42-induced institute of cancer research (ICR) mice. By conducting a Y-maze, passive avoidance, and Morris water maze tests with amyloidogenic mice, it was found that walnut extract ameliorated behavioral dysfunction and memory deficit. The walnut extract showed a protective effect on the antioxidant system and cholinergic system by regulating malondialdehyde (MDA) levels, superoxide dismutase (SOD) contents, reduced glutathione (GSH) contents, acetylcholine (ACh) levels, acetylcholinesterase (AChE) activity, and protein expression of AChE and choline acetyltransferase (ChAT). Furthermore, the walnut extract suppressed Aβ-induced abnormality of mitochondrial function by ameliorating reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and ATP contents. Finally, the walnut extract regulated the expression of zonula occludens-1 (ZO-1) and occludin concerned with blood–brain barrier (BBB) function, expression of tumor necrosis factor-alpha (TNF-α), tumor necrosis factor receptor 1 (TNFR1), phosphorylated c-Jun N-terminal kinase (p-JNK), phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (p-IκB), cyclooxygenase-2 (COX-2), and interleukin 1 beta (IL-1β), related to neuroinflammation and the expression of phosphorylated protein kinase B (p-Akt), caspase-3, hyperphosphorylation of tau (p-tau), and heme oxygenase-1 (HO-1), associated with the Aβ-related Akt pathway.

Insights from vaccinia virus into Toll-like receptor signalling proteins and their regulation by ubiquitin: role of IRAK-2

2008 ◽  
Vol 36 (3) ◽  
pp. 449-452 ◽  
Author(s):  
Andrew G. Bowie
Keyword(s):  
Vaccinia Virus ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Tumour Necrosis Factor Receptor ◽  
Relative Role ◽  
Toll Like Receptor ◽  
Turn On ◽  
Receptor Signalling ◽  
Necrosis Factor

TLRs (Toll-like receptors) are an important class of pathogen-sensing proteins, which signal the presence of a pathogen by activating transcription factors, such as NF-κB (nuclear factor κB). The TLR pathway to NF-κB activation involves multiple phosphorylation and ubiquitination events. Notably, TRAF-6 [TNF (tumour necrosis factor)-receptor-associated factor-6] Lys63 polyubiquitination is a critical step in the formation of signalling complexes, which turn on NF-κB. Here, the relative role of different IRAKs [IL-1 (interleukin 1)-receptor-associated kinases] in NF-κB activation is discussed. Further, I demonstrate how understanding one molecular mechanism whereby vaccinia virus inhibits NF-κB activation has led to a revealing of a key role for IRAK-2 in TRAF-6-mediated NF-κB activation.

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